Although a significant number of substances are known to have antitumor activity, problems have persisted in many cases in developing compositions and methods for safely and effectively delivering such substances to tumor cells. The general toxicity of many anticancer agents prevents their being administered in free form in the body. Many anticancer agents are not sufficiently soluble or stable in the aqueous environment to allow injection or other effective administration. Furthermore, it is frequently useful to control the size of delivery agents in order to achieve targeting to tumor cells or to allow filtration for the purpose of removing deleterious components such as bacteria. It is also important to achieve a composition which, apart from being non-toxic, is biocompatible.
Phospholipid-encapsulated delivery vehicles have been used to overcome such problems in certain cases. It is known, for example, that some aqueous-insoluble drugs can be incorporated into the lipophilic region within the phospholipid bilayer of a liposome to achieve an aqueous-soluble, relatively non-toxic and biocompatible delivery vehicle. Not all aqueous-insoluble materials are susceptible to such a composition, however.
Hexamethylmelamine (HXM) is an example of an anticancer agent which has received only limited use due to its poor aqueous solubility. Oral administration of HXM yields variable absorption and erratic drug concentrations in the plasma. Ames et al., Cancer Treatment Reports, Vol. 66, No. 7, pp. 1579-1581 (July 1982). Gentisate and hydrochloride salts of HXM have resulted in severe local irritation upon intravenous administration to humans. Recent attempts to formulate HXM in an intravenously-acceptable preparation have focused on incorporating the drug into fat emulsions, and have achieved HXM concentrations of 2 mg/ml or more. Intraperitoneal formulations have also focused on fat emulsions such as that formed with the oil emulsion vehicle Intralipid (Cutter Laboratories, Berkeley, Calif.), discussed by Wickes et al., in Cancer Treatment Reports, Volume 69, No. 6, pp. 657-662 (June 1985). Although such formulations succeed in increasing the concentration of HXM to levels suitable for affecting tumor cells, they do not address the problem of targeting tumor cells specifically through use of phospholipid-encapsulated vesicles of an appropriate size. Nor do they address the problem of sterilization where the medicinal or other component may not be heat-stable since such a preparation can not be sterile filtered.
Accordingly, it is an object of the present invention to provide new compositions for the formulation and delivery of aqueous-insoluble medicinal agents to the body. In one aspect, the invention provides compositions for the formulation and delivery of anticancer agents, including hexamethylmelamine.
It is another object of the present invention to provide methods for manufacturing, sterilization and use of such compositions to deliver medicinal agents to the body, and in particular to tumor cells.